DESCRIPTION: The etiology of pancreatic cancer is not well known. The only known causative environmental agent for cancer of the pancreas is tobacco smoke. The higher rates of pancreatic cancer among smokers and the induction of pancreatic tumors in laboratory animals upon administration of the tobacco-specific nitrosamines (TSNA) 4- (methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and 4- methylnitrosamino)-1-(3-pyridyl)-1-butalol (NNAL) suggest that these tobacco-specific carcinogens may be involved in the etiology of this disease in humans. It is the applicant's hypothesis that TSNAs are delivered to the pancreas, most likely via the blood stream, whereupon metabolic activation may initiate the oncogenic process. Preliminary studies indicate the presence of NNK in smokers' pancreatic juice. The goal of this proposal, which combines clinical investigations with laboratory studies, is to unequivocally confirm the presence of this carcinogen in human pancreatic juice, to study the mechanism involved in its genotoxic activity, and to assess damage to pancreatic DNA. The specific aims are to: (i) Quantify the TSNA, especially NNK and its major metabolite NNAL in pancreatic juice of active smokers, non-smokers possibly exposed to environmental tobacco smoke (ETS), and ETS-unexposed non-smokers, (ii) determine the capacity of human pancreatic microsomes and cytosol to metabolize TSNA and to identify specific cytochrome P450 enzymes in these microsomal preparations that are known to metabolize NNK and (iii) assess levels of TSNA-derived DNA adducts in human histologically normal, non-involved pancreatic tissue. Identification of representative carcinogenic TSNA in pancreatic juice of smokers, demonstration of the capacity of pancreatic tissue to metabolize such carcinogens to DNA-damaging species, and confirmation of established mutagenic lesions in this organ may provide important information requisite to link tobacco smoking and pancreatic cancer.